Analgesics for nasal administration

ABSTRACT

An analgesic and a delivery agent are combined in a pharmaceutical composition such that, on introduction into the nasal cavity of a patient to be treated, the analgesic may be delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration, C ther , of 0.2 ng/ml or greater which is maintained for a duration T maint  of at least 2 hours. The analgesic may be an opioid analgesic or a non-steroidal anti-inflammatory drug.

FIELD OF THE INVENTION

The invention relates to analgesic compositions and their use.

BACKGROUND OF THE INVENTION

A wide variety of compounds can act as analgesics. Two important classesof analgesics are opioid analgesics and non-steroidal anti-inflammatorydrugs (NSAIDs).

Opioid analgesics exhibit morphine-like properties. Opioids can besub-classified on the basis of their receptor specificity. Mu-agonistopioids provide intense analgesia. These opioids can be long-acting(e.g. methadone) or short-acting (e.g. remifentanil). Mixedagonist/antagonist opioids (e.g. butorphanol and buprenorphine) arepartial agonists (the former at mu and kappa receptors and the latter atthe mu receptor) and can produce good quality analgesia. They produceless respiratory depression and constipation than high efficacy muagonists.

As a class, opioids are associated with a number of undesirableside-effects, including respiratory depression, nausea, vomiting,dizziness, mental clouding, dysphoria, pruritus, constipation, increasedbiliary tract pressure, urinary retention and hypotension. Thedevelopment of tolerance and the risk of chemical dependence and abuseare further problems. Buprenorphine, however, is unusual in exhibiting alow maximum effect for respiratory depression and also a bell-shapeddose response curve where the effect first increases with larger doses,reaches a ceiling and then diminishes as the dosage is furtherincreased, which makes it a safer drug than morphine, where respiratorydepression will ultimately lead to death. Buprenorphine has also beenshown to have a lower incidence of other side-effects like constipationin man, and it has a lower abuse potential than full mu agonists.

NSAIDs have anti-inflammatory action and are effective on painassociated with the release of prostaglandins (PG) and other mediatorsof inflammation. They act by blocking the action of cyclooxygenase(COX), which converts arachidonic acid to eicosanoids. The eicosanoidsinclude the prostanoids, prostacyclin (PGI₂), PGE₂ and the thromboxanes.There are at least two COX enzymes: a constitutively-expressed COX-1responsible for producing homeostatic prostaglandin and thromboxanemediators and an inducible COX-2 that is produced in large quantities inresponse to stimuli such as infection and inflammation.

Since the prostaglandins and thromboxanes mediate a number ofhomeostatic and protective mechanisms, toxic side effects often arisefrom the use of NSAIDs as a result of disruption of these mechanisms.These include clotting disorders (leading to prolonged bleeding times)and gastric irritation (including ulceration). NSAIDs may also causesalt and water retention and may therefore exacerbate hypertension. Theymay also be teratogenic at high doses during pregnancy. They arecontra-indicated in patients with peptic ulcers, gastritis, regionalenteritis, ulcerative colitis, diverticulitis, a recurrent history ofgastrointestinal lesions, gastrointestinal bleeding, coagulationdisorders (such as anemia, hypoprothrombinemia and haemophilia), kidneydiseases and in patients about to undergo surgery or takinganticoagulants.

The NSAIDs are associated with a number of adverse effects on thekidneys, although most are rare. The kidney produces PGI₂, PGE₂ and somePGF_(2α). These are involved in local modulation of renal blood flow,glomerular filtration rate, renin release, the concentrating mechanismfor urine and the excretion of sodium and potassium. The unwantedeffects of NSAIDs result from the decrease in production of theprostaglandins and are summarized below:

-   -   1. Acute reversible/vasomotor renal failure.    -   2. Interference with the renal excretion of water, sodium and        potassium.    -   3. Interference with antihypertensive therapy and diuretic        therapy.    -   4. Acute interstitial nephritis with or without renal failure.    -   5. Nephrotic syndrome with or without interstitial nephritis and        renal failure.    -   6. Chronic renal injury (“analgesic nephropathy”).

There is great interest in the development of NSAIDs that are COX-2specific, since such drugs would be expected to permit the treatment ofinflammation and pain without affecting COX-1-mediated gastrointestinalprotection. However, COX-2 inhibitors still show the renal and cardiaceffects of non-selective NSAIDs.

Ideally, pain relief should follow immediately upon administration of ananalgesic. The relief should be maintained for an extended period thatis at least long enough to permit normal unbroken sleep patterns andavoid complicated dosage regimes.

In practice, however, the dynamics of pain relief obtained with currentanalgesic administration technologies does not meet these ideals. Whilerapid onset of pain relief can be achieved by intravenous injection,this mode of administration cannot in general be carried out by thepatient and so is relatively expensive and inconvenient. Moreover,intravenous injection is generally associated with rapid offset of painrelief as the circulating analgesic is cleared from the plasma.Prolonged analgesia requires multiple injections which is inconvenientand expensive. Intravenous injection is also usually associated withrelatively high C_(max) values, which can trigger (or amplify) any sideeffects associated with the analgesic.

While alternative technologies (including intramuscular injection andinhalation) have been developed for effecting rapid onset analgesia,these all rely upon rapid delivery of the bulk of the analgesic doseinto the blood system and so suffer from the same rapid offset problemsassociated with intravenous injection.

Attempts have been made to obviate such problems by providing pumpedanalgesic into the blood supply via a patient-controlled quick-dosepump. While this apparatus has the potential for long-term effectivepain management, it is expensive, does not permit ambulation, requiresextensive monitoring and may interfere with normal sleep patterns(depending on the frequency with which pain prompts the patient tore-dose).

The problem of rapid offset of pain relief has promoted the developmentof sustained release technologies. Such technologies include transdermalpatches and sublingual tablets. However, transdermal patches can causeskin irritation and the drug dosage is difficult to control. Sublingualtablets have an unpleasant taste and must be maintained in the mouth forrelatively long periods of time (often 30 minutes or more), leading tocompliance problems.

However, the principal problem associated with such sustained analgesiatechniques stems from the fact that the onset of pain relief is slow andassociated with a lag time of at least an hour (during which plasmalevels of the analgesic steadily climb towards the therapeuticconcentration threshold). In many applications (especially in caseswhere pain is intense and prolonged) such pain relief dynamics areunacceptable.

Buprenorphine has previously been administered via the intravenous,intramuscular and sublingual routes to human subjects. There are limitedreports of nasal administration. Eriksen et al, J. Pharm. Pharmacol. 41,803-805, 1989 report administration to human volunteers of a nasalspray. The spray consisted of 2 mg/ml of buprenorphine hydrochloridedissolved in 5% dextrose and the pH of the solution was adjusted to pH5.

WO 90/09870 describes a composition for administration to mucosacomprising a pharmacologically active compound and a polycationicsubstance such as DEAE-dextran or chitosan. WO 98/47535 discloses asingle component liquid pharmaceutical composition for administration toa mucosal surface. The composition comprises a therapeutic agent, apectin with a low degree of esterification and an aqueous carrier thatgels or can be adapted to gel at the site of application. Neither WO90/09780 nor WO 98/47535 mentions buprenorphine.

SUMMARY OF THE INVENTION

Improved analgesic formulations for nasal administration have now beendevised. Rapid uptake of the analgesic across the nasal mucosa into theplasma can be achieved, which results in fast onset of analgesia.Further, the residence time of the analgesic in the nasal cavity can beincreased, which results in prolonged analgesia. An improved profile ofabsorption of the analgesic into the systemic circulation can thus beachieved.

Accordingly, the present invention provides use of an analgesic and adelivery agent for the manufacture of a medicament for administrationintranasally for the treatment of pain whereby, on introduction into thenasal cavity of a patient to be treated, the analgesic is delivered tothe bloodstream to produce within 30 minutes a therapeutic plasmaconcentration C_(ther) of 0.2 ng/ml or greater which is maintained for aduration T_(maint) of at least 2 hours.

The invention thus enables a therapeutic blood plasma concentration ofan analgesic, i.e. a concentration that produces pain relief or painamelioration, to be attained within 30 minutes and maintained for up to24 hours. The term C_(ther) denotes a therapeutic blood plasmaconcentration. The term T_(maint) denotes the duration for whichC_(ther) is maintained. Also provided are:

-   -   use of a pharmaceutical composition which comprises an analgesic        and a delivery agent for the manufacture of a nasal delivery        device for use in inducing analgesia whereby, on introduction        into the nasal cavity of a patient to be treated, the analgesic        is delivered to the bloodstream to produce within 30 minutes a        therapeutic plasma concentration C_(ther) of 0.2 ng/ml or        greater which is maintained for a duration T_(maint) of at least        2 hours;    -   a pharmaceutical composition which comprises an analgesic and a        delivery agent whereby, on introduction into the nasal cavity of        a patient to be treated, the analgesic is delivered to the        bloodstream to produce within 30 minutes a therapeutic plasma        concentration C_(ther) of 0.2 ng/ml or greater which is        maintained for a duration T_(maint) of at least 2 hours; and    -   a method of inducing analgesia in a patient in need thereof,        which method comprises administering intranasally to said        patient a pharmaceutical composition which comprises an        analgesic and a delivery agent whereby, on introduction into the        nasal cavity of said patient to be treated, the analgesic is        delivered to the bloodstream to produce within 30 minutes a        therapeutic plasma concentration C_(ther) of 0.2 ng/ml or        greater which is maintained for a duration T_(maint) of at least        2 hours.

The invention further provides:

-   -   (1) an aqueous solution suitable for intranasal administration,        which comprises:        -   (a) from 0.1 to 10 mg/ml of buprenorphine or a            physiologically acceptable salt or ester thereof,        -   (b) from 0:1 to 20 mg/ml of a chitosan, and        -   (c) from 0.1 to 15 mg/ml of hydroxypropylmethylcellulose            (HPMC);        -   which solution has a pH of from 3 to 4.8;    -   (2) an aqueous solution suitable for intranasal administration,        which comprises:        -   (a) from 0.1 to 10 mg/ml of buprenorphine or a            physiologically acceptable salt or ester thereof,        -   (b) from 0.1 to 20 mg/ml of a chitosan, and        -   (c) from 50 to 200 mg/ml of a            polyoxyethylene-polyoxypropylene copolymer of the general            formula HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H wherein a is            from 2 to 130 and b is from 15 to 67;        -   which solution has a pH of from 3 to 4.8; and    -   (3) an aqueous solution suitable for intranasal administration,        which comprises from 0.1 to 10 mg/ml of buprenorphine or a        physiologically acceptable salt or ester thereof and from 5 to        40 mg/ml of a pectin having a degree of esterification of less        than 50%; which solution has a pH of from 3 to 4.2, is        substantially free from divalent metal ions and gels on the        nasal mucosa.        -   A preferred solution of the invention has a pH of from 3.5            to 4.0, is substantially free from divalent metal ions and            comprises:        -   (a) from 1 to 6 mg/ml of buprenorphine or a physiologically            acceptable salt or ester thereof, calculated as            buprenorphine,        -   (b) from 10 to 40 mg/ml of a pectin which has a degree of            esterification from 10 to 35%, and        -   (c) dextrose as a tonicity adjustment agent.

The invention also provides:

-   -   a process for the preparation of solution (1), which comprises        dissolving buprenorphine or a physiologically acceptable salt or        ester thereof, a chitosan and HPMC in water to provide a        solution comprising from 0.1 to 10 mg/ml of buprenorphine or        said salt or ester thereof, from 0.1 to 20 mg/ml of chitosan and        from 0.1 to 15 mg/ml of HPMC; and adjusting the pH of the        solution to a value from 3 to 4.8 as desired;    -   a process for the preparation of solution 2), which comprises        dissolving buprenorphine or a physiologically acceptable salt or        ester thereof, a chitosan and a polyoxyethylene-polyoxypropylene        copolymer of the general formula        HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H wherein a is from 2 to 130        and b is from 15 to 67, in water to provide a solution        comprising from 0.1 to 10 mg/ml of buprenorphine or said salt or        ester thereof, from 0.1 to 20 mg/ml of a chitosan and from 50 to        200 mg/ml of the polyoxyethylene-polyoxypropylene copolymer; and        adjusting the pH of the solution to a value from 3 to 4.8 as        desired;    -   a process for the preparation of solution (3), which comprises        dissolving buprenorphine or a physiologically acceptable salt or        ester thereof in water; mixing the resulting solution with a        solution in water of a pectin having a degree of esterification        of less than 50% such that the mixed solution comprises from 0.1        to 10 mg/ml of buprenorphine or said salt or ester thereof and        from 5 to 40 mg/ml of the pectin; and adjusting the pH of the        solution to a value from 3 to 4.2 if desired;    -   a nasal delivery device loaded with a solution of the invention;    -   use of a solution of the invention for the manufacture of a        nasal delivery device for use in inducing analgesia; and    -   a method of inducing analgesia in a patient in need thereof,        which method comprises intranasally administering a solution of        the invention to the patient.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1 to 3 show the pharmacokinetic profiles that were obtained whenbuprenorphine formulations according to the invention (Formulations A toC) were administered intranasally to healthy volunteers at a dose of 800μg of buprenorphine hydrochloride, calculated as buprenorphine.Formulation A: buprenorphine hydrochloride-pectin solution. FormulationB: buprenorphine hydrochloride-chitosan/hydroxypropylmethylcellulose(HPMC) solution. Formulation C: buprenorphinehydrochloride-chitosan/poloxamer 188 solution. Also shown for comparisonis the pharmacokinetic profile that was obtained when a commercialsolution of buprenorphine hydrochloride (Terngesic—trade mark;Formulation D) was administered intravenously to healthy volunteers inthe same study at a dose of 400 μg of buprenorphine hydrochloride,calculated as buprenorphine.

FIG. 4 shows a pharmacokinetic profile for a 400 μg dose of FormulationA. This profile was calculated from the data for the 800 μg dose ofFormulation A. The pharmacokinetic profile for the 400 μg dose ofFormulation D is also shown for comparison.

DETAILED DESCRIPTION OF THE INVENTION

The invention is concerned with analgesic compositions that aredelivered intranasally to achieve fast onset of analgesia and alsoprolonged analgesia. An advantageous pharmacokinetic profile cantherefore be attained. An analgesic is combined with a delivery agentwhich is selected so that, on introduction into the nasal cavity of apatient to be treated, the analgesic is delivered to the bloodstream toproduce within 30 minutes a therapeutic plasma concentration C_(ther) of0.2 ng/ml or greater which is maintained for a duration T_(maint) of atleast 2 hours. This effect may be achieved by administration of a singledose of the analgesic, or following multiple dosing.

The compositions of the invention are adapted to enable the analgesic tobe delivered such that a C_(ther) of 0.2 ng/ml or more, for example 0.4ng/ml or more, is attained within 30 minutes after introduction into thenasal cavity such as within 0.5 to 20 minutes, for example 2 to 15minutes or 5 to 10 minutes. The term C_(ther) defines a therapeuticplasma concentration (or range thereof). Thus, the term is used hereinto define a blood plasma concentration (or range of plasmaconcentrations) of the analgesic that produces pain relief or painamelioration.

Depending upon the analgesic, C_(ther) may be up to 100 ng/ml such asfrom 0.4 ng/ml to 80 mg/ml. For potent analgesics, C_(ther) may be from0.4 ng/ml to 20 ng/ml. For less potent analgesics, C_(ther) may be from20 to 100 ng/ml such as from 50 to 80 ng/ml. These C_(ther) values applyespecially to opioid analgesics. For the potent opioid analgesicbuprenorphine, C_(ther) may be from 0.4 to 5 ng/ml, for example 0.5 to 4ng/ml or 0.8 to 2 ng/ml.

T_(maint) is typically at least 2 hours. The term T_(maint) defines theduration of maintenance of C_(ther) after administration of theanalgesic. For example, the T_(maint) can be from up to 24 hours, up to12 hours or up to 6 hours such as from 2 to 4 hours or 2 to 3 hours. Bymeans of the invention, therefore, a C_(ther) of at least 0.4 ng/ml maybe attained within 2 to 15′ minutes and maintained for a time periodT_(maint) of from 2 to 4 hours.

As already mentioned, rapid onset of analgesia and prolonged analgesiacan be achieved. The analgesic delivery profile that can be attained mayavoid the relatively high C_(max) values associated with intravenousadministration and so lead to an improved therapeutic index. The peakplasma concentration of an analgesic that is attained afteradministration is defined as C_(max). The invention can permit reductionor elimination of some or all of the side effects associated with theanalgesic.

C_(max) depends upon the analgesic. C_(max) is typically from 1 to 500ng/ml or higher, for example from 1.5 to 400 ng/ml or from 1.5 to 100ng/ml. For potent analgesics, C_(max) may be from 1.5 to 50 ng/ml. Forless potent analgesics, C_(max) may be from 50 to 500 ng/ml such as from50 to 200 ng/ml or 50 to 100 ng/ml. These C_(max) values applyespecially to opioid analgesics. For buprenorphine, C_(max) is typicallyfrom 1 to 5 ng/ml, for example from 1 to 4 ng/ml or from 1.5 to 3 ng/ml.C_(max) may be from 1 to 2 ng/ml, especially for lower doses. The timeat which C_(max) is reached (T_(max)) is typically 10 to 40 minutesafter administration, for example 10 to 30 minutes or 15 to 25 minutessuch as 15 to 20 minutes.

In preferred embodiments, the delivery agent is adapted to deliver theanalgesic component such that C_(max)=C_(opt). The term C_(opt) is usedin relation to analgesic drugs which exhibit a dose-response curve toanalgesia which is displaced to the left with respect to thedose-response curve for side-effects. The term defines a therapeuticplasma concentration or range thereof which produces acceptable painrelief or pain amelioration but which does not produce side-effects orproduces side effects which are less than those associated with higherplasma concentrations.

The analgesic may be an opioid analgesic. It may be a mixedagonist/antagonist such as a mixed mu-agonist/antagonist (also known asa partial agonist) or a mixed mu- and kappa-agonist/antagonist. It maybe a mu-agonist. A preferred opioid analgesic is buprenorphine or aphysiologically acceptable salt or ester thereof. Buprenorphine(Chemical Abstracts Registration No. (CAS RN) 52485-79-7;[5α,7α(S)-17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanol)has the formula:

The buprenorphine salt may be an acid addition salt or a salt with abase. Suitable acid addition salts include the hydrochloride, sulphate,methane sulphonate, stearate, tartrate and lactate salts. Thehydrochloride salt is preferred (CAS RN 53152-21-9)

Other suitable opioid analgesics include alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, butorphanol,clonitazene, cyclazocine, desomorphine, dextromoramide, dezocine,diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalbuphine, nalorphine,naloxone, naltrexone, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, profadol,propheptazine, promedol, properidine, propiram, propoxyphene,sufentanil, tilidine and tramadol. Also included are esters, salts andmixtures of any of the foregoing.

The salts for use in the invention may be any physiologically acceptablesalts, including pharmaceutically acceptable acid addition salts.Examples include hydrochloride salts (for example the hydrochloridesalts of nalbuphine, profadol, buprenorphine, morphine, pentazocine,naloxone and nalorphine) as well as levorphanol tartrate, nalorphinehydrobromide, levallorphan tartrate, morphine sulfate, butorphanoltartrate, pentazocine lactate and phenazocine hydrobromide.

The analgesic may be a non-opioid analgesic such as a NSAID, a tricylicantidepressant (e.g. amitryptyline), an anticonvulsant (e.g. gabapentin)or an antimigraine compound (e.g. sumatriptan or naratriptan). The NSAIDmay be a cyclooxygenase (COX) COX-1 or COX-2 inhibitor. Specificexamples of NSAIDs include ibuprofen, flurbiprofen, diclofenac,indomethacin, piroxicam, ketoprofen, etodolac, diflusinal, meloxicam,aceclofenac, fenoprofen, naproxen, tiaprofenic acid, tolmetin, celecoxiband rofecoxib, and their physiologically acceptable salts and esters.Suitable salts are alkali addition salts such as the potassium or sodiumsalt.

A preferred NSAID is diclofenac (CAS RN 15307-86-5;2-[(2,6-dichlorophenyl)amino]benzeneacetic acid) or a physiologicallyacceptable salt or ester thereof. Diclofenac has the formula:

Diclofenac is available in various forms. Diclofenac Sodium (CAS RN15307-79-60; 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid sodiumsalt) is sold under the following trade marks: Allorvan, Benfofen,Dealgic, Deflamat, Delphinac, Diclomax, Diclometin, Dichlophlogont,Diclo-Puren, Dicloreum, Diclo-Spondyril, Dolobasan, Duravolten,Ecofenac, Effekton, Lexobene, Motifene, Neriodin, Novapirina,Primofenac, Prophenatin, Rewodina, Rhumalgan, Trabona, Tsudohmin,Valetan, Voldal, Voltaren and Xenid. Diclofenac Potassium (CAS RN15307-81-0; 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid potassiumsalt) is also known as Cataflam (trade mark).

Another preferred NSAID is etodolac (CAS RN 41340-25-4;1,8-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid) or aphysiologically acceptable salt or ester thereof. Etodolac is sold underthe trade marks Etogesic, Lodine, Tedolan and Ultradol. Etodolac has theformula:

Further preferred NSAIDs are piroxicam and meloxicam, andphysiologically acceptable salts and esters thereof. Piroxicam (CAS RN36322-90-4;4-Hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide.1,1-dioxide) is sold under the trade mark Feldine, Sinartrol, Zelis,Zen, Brexin, Cicladol or Cycladol and has the formula:

Meloxicam (CAS RN 71125-38-7;4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide has the formula:

The analgesic is provided in a formulation suitable for nasaladministration in combination with a delivery agent. The formulation istypically a liquid formulation, especially as an aqueous solution.Alternatively, the formulation may be in the form of a powder ormicrospheres.

When the formulation is a liquid formulation, the concentration ofbuprenorphine or buprenorphine salt or ester is from 0.1 to 10 mg/ml,for example from 0.5 to 8 mg/ml. Preferred concentrations are 1 to 6mg/ml, for example 1 to 4 mg/ml calculated as buprenorphine. Suitableformulations can contain buprenorphine or a buprenorphine salt or esterin an amount of 1 mg/ml or 4 mg/ml, calculated as buprenorphine.

The delivery agent is selected so that rapid onset and prolongedanalgesia is obtained. The delivery agent acts to deliver the analgesicto the bloodstream. Thus, the delivery agent acts as an analgesicabsorption modifier and any of a wide variety of delivery agents may beused providing that this functional requirement is met.

The delivery agent may comprise an absorption promoting agent. Suchagents promote uptake of the analgesic component into the bloodstream.They may act via a variety of different mechanisms. Particularlypreferred are mucosal adhesives. Such adhesives maintain an intimateassociation between the bulk analgesic composition and the nasal mucosa,so enhancing absorption and extending the T_(maint) of the analgesiccomponent. They can also be used to lower the analgesic C_(max) whichmay be important in applications where the minimization or eliminationof side-effects is desired.

Suitable absorption promoting agents include cationic polymers(particularly chitosans), surface active agents, fatty acids, chelatingagents, mucolytic agents, cyclodextrins, diethylaminoethyl-dextran(DEAE-dextran; a polycationic derivative of dextran) or combinationsthereof. Particularly preferred are pectins having a degree ofesterification of less than 50%, especially from 10 to 35%, andchitosans.

The composition of the invention takes the form of an aqueous solutionwhen the delivery agent is a pectin. The pectin acts as a gelling agent.A pectin-containing composition of the invention gels on the mucosalsurfaces of the nasal cavity after delivery without the need for anextraneous source of divalent metal ions. The analgesic that isformulated with the pectin is thus retained for longer on the surfacesof the nasal epithelium. The resulting sustained release of theanalgesic into the bloodstream enables prolonged analgesia to beachieved. Improved delivery of the analgesic can consequently beobtained. Rapid uptake of the analgesic also results, which leads tofast onset of analgesia.

The pectins employed in the invention have a degree of esterification ofless than 50%. A pectin is a polysaccharide substance present in thecell walls of all plant tissues. Commercially pectins are generallyobtained from the dilute acid extract of the inner portion of the rindof citrus fruits or from apple pomace. A pectin consists of partiallymethoxylated polygalacturonic acids. The proportion of galacturonic acidmoieties in the methyl ester form represents the degree ofesterification (DE). The term DE is well understood by those skilled inthe art and may be represented as the percentage of the total number ofcarboxyl groups that are esterified, i.e. if four out of five acidgroups is esterified this represents a degree of esterification of 80%,or as the methoxyl content of the pectin. DE as used herein refers tothe total percentage of carboxyl groups that are esterified. Pectins canbe categorised into those having a low degree of esterification (lowmethoxylation) or a high degree of esterification (high methoxylation).A “low DE” or “LM” pectin has a degree of esterification below 50%whereas a “high DE” or “HM” pectin has a degree of esterification of 50%or above. The gelling properties of aqueous pectin solutions can becontrolled by the concentration of pectin, the type of pectin,especially the degree of esterification of the galacturonic acid units,and the presence of added salts.

Low DE pectins are used in the present invention. The primary mechanismby which such pectins gel in aqueous solution is through exposure tometal ions, such as those found in the nasal mucosal fluid as describedin WO 98/47535. The degree of esterification of the pectin used in theinvention is preferably less than 35%. The degree of esterification maythus be from 10 to 35%, for example from 15 to 25%. Low DE pectins maybe purchased commercially. An example of a low DE pectin is SLENDID(trade mark) 100, supplied by CP Kelco (Lille Skenved) which has adegree of esterification of around 15 to 25%.

A pectin-containing solution of the invention must not gel on storage.It should not gel prior to application to the nasal cavity. It musttherefore be substantially free of agents which would cause the solutionto gel. In particular, a solution of the invention must be substantiallyfree of divalent metal ions and especially calcium ions. The content ofdivalent metal ions in the solution must therefore be minimised. Apectin-containing solution of the invention may therefore contain anegligible concentration of divalent metal ions or there may nodetectable divalent metal ions.

A pectin is typically present in a solution of the invention at aconcentration of from 5 to 40 mg/ml, for example from 5 to 30 mg/ml.More preferably, the pectin concentration is from 10 to 30 ng/ml or from10 to 25 mg/ml. The pectin and the pectin concentration are selectedsuch that the solution gels on delivery to the nasal mucosa. Thesolution gels on the nasal mucosa in the absence of an extraneous sourceof divalent metal ions, e.g. Ca²⁺ ions.

The composition of the invention also takes the form of an aqueoussolution when the delivery agent is a chitosan. Chitosans are cationicpolymers that have mucoadhesive properties. The mucoadhesion is thoughtto result from an interaction between the positively charged chitosanmolecule and the negatively charged sialic acid group's on mucin (Soaneet al, Int. J. Pharm 178, 55-65, 1999).

By the term “chitosan” we include all derivatives of chitin, orpoly-N-acetyl-D-glucosamine, including all polyglucosamines andoligomers of glucosamine materials of different molecular weights, inwhich the greater proportion of the N-acetyl groups have been removedthrough hydrolysis (deacetylation). Preferably, the chitosan is producedfrom chitin by deacetylation to a degree of greater than 40%, preferablybetween 50 and 98%, more preferably between 70% and 90%.

The chitosan typically has a molecular weight of 4,000 Da or more,preferably from 10,000 to 1,000,000 Da, more preferably from 15,000 to750,000 Da and most preferably from 50,000 to 500,000 Da.

The chitosan may thus be a deacetylated chitin. It may be aphysiologically acceptable salt. Suitable physiologically acceptablesalts include salts with a pharmaceutically acceptable mineral ororganic acid such as the nitrate, phosphate, lactate, citrate,hydrochloride and acetate salts. Preferred salts are chitosan glutamateand chitosan hydrochloride.

The chitosan may be a derivative of a deacetylated chitin. Suitablederivatives include, but are not limited to, ester, ether or otherderivatives formed by bonding of acyl and/or alkyl groups with thehydroxy groups, but not the amino groups, of a deacetylated chitin.Examples are O—(C₁-C₆ alkyl)ethers of deacetylated chitin and O-acylesters of deacetylated chitin. Derivatives also include modified formsof a deacetylated chitin for example a deacetylated chitin conjugated topolyethylene glycol.

Low and medium viscosity chitosans suitable for use in the presentinvention may be obtained from various sources, including FMCBiopolymer, Drammen, Norway; Seigagaku America Inc., Maryland, USA;Meron (India) Pvt, Ltd., India; Vanson Ltd, Virginia, USA; and AMSBiotechnology Ltd., UK. Suitable derivatives include those that aredisclosed in Roberts, Chitin Chemistry, MacMillan Press Ltd., London(1992). Particularly preferred chitosan compounds that may be mentionedinclude “Protosan” (trade mark) available from FMC Biopolymer, Drammen,Norway. The chitosan is preferably water-soluble.

An aqueous solution of chitosan may be prepared by dissolving chitosanbase or a derivative of chitosan base in a pharmaceutically acceptablemineral or organic acid such as hydrochloric, lactic, citric or glutamicacid or by dissolving a chitosan salt in water.

The chitosan is typically present in solution at a concentration of from0.1 to 20 mg/ml, for example from 0.5 to 20 mg/ml. Preferably thesolution contains from 1 to 15 mg/ml, more preferably from 2 to 10mg/ml, of chitosan. A chitosan concentration of 5 mg/ml is particularlysuitable.

Chitosan-containing solutions of the invention may also containhydroxypropylmethylcellulose (HPMC) or apolyoxyethylene-polyoxypropylene copolymer.

Any suitable HPMC may be employed. Several grades of HPMC are available.For example, Dow Chemical Company produces a range of HPMC polymersunder the trade mark Methocel. The grade and concentration of HPMC ischosen such that the solution of the invention preferably has aviscosity, at 25° C. as measured by a cone and plate viscometer (e.g.Brookfield), in the range from 1 to 200 cps, more preferably from 3 to150 cps and most preferably from 5 to 100 cps.

Producing a solution having a particular viscosity is within thecapability of one skilled in the at and can be achieved, for example, byusing a high concentration of a low viscosity HPMC or a lowconcentration of a high viscosity HPMC. The HPMC is preferably onehaving an apparent viscosity (measured as a 2% solution in water at 20°C.) in the range from 3000 to 6000 cps. The concentration of the HPMChaving a viscosity of from 3000 to 6000 cps is typically in the rangefrom 0.1 to 15 mg/ml, for example from 0.5 to 10 mg/ml and preferablyfrom 1 to 5 mg/ml.

The polyoxyethylene-polyoxypropylene copolymer typically has a molecularweight of from 2,500 to 18,000 for example from 7,000 to 15,000. Thecopolymer is a block copolymer of the general formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H

wherein a is from 2 to 130 and b is from 15 to 67. The value for a maybe from 40 to 100 such as from 60 to 90 or from 70 to 95. The value forb may be from 20 to 40 such as from 25 to 35.

Such copolymers are known as poloxamers. Several different types ofpoloxamer are available commercially, from suppliers such as BASF, andvary with respect to molecular weight and the proportions of ethyleneoxide “a” units acid propylene oxide “b” units. A commercially availablepoloxamer suitable for use in the present invention is poloxamer 188which structurally contains 80 “a” units and 27 “b” units and has amolecular weight of 7680-9510 (Handbook of Pharmaceutical Excipients,editor A. H. Kippe, third edition, Pharmaceutical Press, London, UK,2000). Preferably the poloxamer is poloxamer 188.

The polyoxyethylene-polyoxypropylene copolymer is typically present inan amount of from 50 to 200 mg/ml, preferably from 65 to 160 mg/ml andmore preferably from 80 to 120 mg/ml. A preferred concentration is 100mg/ml.

Other cationic polymers besides chitosans suitable for use as absorptionpromoting agents include polycationic carbohydrates. The polycationicsubstances preferably have a molecular weight of at least 10,000. Theymay be in liquid formulations at concentrations of 0.01 to 50% w/v,preferably 0.1 to 50% w/v and more preferably 0.2 to 30% w/v.

Examples of suitable polycationic polymers are polyaminoacids (e.g.polylysine), polyquaternary compounds, protamine, polyamine, DEAE-imine,polyvinylpyridine, polythiodiethyl-aminomethylethylene, polyhistidine,DEAE-methacrylate, DEAF-acrylamide, poly-p-aminostyrene, polyoxethane,co-polymethacrylates (e.g. copolymers of HPMA,N-(2-hydroxypropyl)-methacrylamide), GAFQUAT (see for example U.S. Pat.No. 3,910,862) and polyamidoamines.

Suitable surface active agents for use according to the presentinvention are bile salts (for example sodium deoxycholate andcholylsarcosine, a synthetic N-acyl conjugate of cholic acid withsarcosine [N-methylglycine]). Also suitable for use in the invention arebile salt derivatives (for example sodium tauro dihydrofusidate). Any ofa wide range of non-ionic surfactants (e.g. polyoxyethylene-9 laurylether), phospholipids and lysophosphatidyl compounds (e.g. lysolecithin,lysophosphatidyl-ethanolamine, lysophosphatidylcholine,lysophosphatidylglycerol, lysophosphatidylserine and lysophosphatidicacid) may also be used. Water-soluble phospholipids may also be employed(e.g. short chain phosphatidylglycerol and phosphatidylcholines). Theconcentration of surface active agents used according to the inventionvaries according to the physico-chemical properties of the surfaceactive agent selected, but typical concentrations are in the range 0.02to 10% w/v.

Particularly preferred surface active agents for use as absorptionpromoting materials are phospholipids and lysophosphatides (hydrolysisproducts of phospholipids), both of which form micellar structures.

When microspheres are used as the delivery agent, they are preferablyprepared from a biocompatible material that will gel in contact with themucosal surface: Substantially uniform solid microspheres are preferred.Starch microspheres (crosslinked if necessary) are preferred.

Microspheres may also be prepared from starch derivatives, modifiedstarches (such as amylodextrin), gelatin, albumin, collagen, dextran anddextran derivatives, polyvinyl alcohol, polylactide-co-glycolide,hyaluronic acid and derivatives thereof (such as benzyl and ethylesters), gellan gum and derivatives thereof (such as benzyl and ethylesters) and pectin and derivatives thereof (such as benzyl and ethylesters). The term “derivative” covers inter alia esters and ethers ofthe parent compound, which can be functionalised (for example toincorporate ionic groups).

Any of a wide variety of commercially available starch derivatives maybe used, including hydroxyethyl starch, hydroxypropyl starch,carboxymethyl starch, cationic starch, acetylated starch, phosphorylatedstarch, succinate derivatives of starch and grafted starches.

Suitable dextran derivatives include, diethylaminoethyl-dextran(DEAE-dextran), dextran sulphate, dextran methyl-benzylamidesulphonates, dextran methyl-benzylamide carboxylates, carboxymethyldextran, diphosphonate dextran, dextran hydrazide, palmitoyldextran anddextran phosphate.

The preparation of microspheres for use according to the invention maybe carried out by known processes, including emulsion and phaseseparation methods (see for example Davis et al., (Eds), “Microspheresand Drug Therapy”, Elsevier Biomedical Press, 1984, which parts relatingto microsphere preparation are incorporated herein by reference). Forexample, albumin microspheres may be made using the water-in-oilemulsification method where a dispersion of albumin in oil is producedby homogenization or stirring, with the addition if necessary of smallamounts of an appropriate surface active agent.

The size of the microspheres is largely determined by the speed ofstirring or the homogenization conditions. Agitation can be provided bya simple laboratory stirrer or by more sophisticated devices (such asmicrofluidizers or homogenisers). Emulsification techniques may also beused to produce starch microspheres (as described in GB 1518121 and EP223303) and for the preparation of gelatin microspheres.

Proteinaceous microspheres may be prepared by coacervation methods. Suchmethods include simple or complex coacervation as well as phaseseparation techniques (using solvents or electrolyte solutions). Suchmethods are well known to those skilled in the art and details may befound in standard textbooks (for example Florence and Attwood,Physicochemical Principles of Pharmacy 2nd Ed., MacMillan Press, 1988,Chapter 8).

The microspheres may advantageously have controlled-release properties,which may be conferred by modifications of the microspheres (for exampleby controlling the degree of cross-linking or by the incorporation ofexcipients that alter the diffusional properties of the analgesiccomponent). Alternatively, controlled release properties may beincorporated by exploiting ion-exchange chemistry (for exampleDEAE-dextran and chitosan are positively charged and can be used for anion-exchange interaction with metabolites that are negatively charged).

The maximum amount of analgesic component that can be carried by themicrospheres is termed the loading capacity. It is determined by thephysico-chemical properties of the analgesic component and in particularits size and affinity for the matrix of the microspheres. High loadingcapacities can be achieved when the analgesic is incorporated into themicrospheres during microsphere manufacture.

Microcapsules (which may be bioadhesive and which may also exhibitcontrolled release properties) may also be employed as an absorptionpromoting agent in the compositions of the invention. Thesemicrocapsules can be produced by a variety of methods. The surface ofthe capsule may be inherently adhesive or can be modified by standardcoating methods known to those skilled in the art. Suitable coatingmaterials include bioadhesive polymers such as polycarbophil, carbopol,DEAE-dextran, alginate, microcrystalline cellulose, dextran,polycarbophils and chitosan).

Oil-in-water formulations can provide for the effective nasal deliveryof analgesics that are poorly soluble in water. In such applicationsnasal irritation may also be reduced.

The oil phase of the emulsions of the invention may comprise ahydroxylated oil, particularly a hydroxylated vegetable oil. As usedherein the term “hydroxylated oil” is intended to cover any oil thatcontains hydroxylated fatty acids. Preferred hydroxylated oils arehydroxylated vegetable oils, and a preferred hydroxylated vegetable oilfor use in the present composition is castor oil.

As used herein, the term “castor oil” is intended to include ricinusoil, oil of Palma Christie, tangantargon oil and Neoloid (as describedin Merck Index, 12th Edition, p: 311), as well as the oil from RicinusZanzibarinus. The latter has a high content of glycerides of ricinoleicacid. Thus, castor oil comprises glycerides of ricinoleic acid (ahydroxy fatty acid).

When castor oil is used in the present invention, it may conveniently beobtained by cold pressing of the seeds of Ricinus Communis L. (family:Euphorbiaceae).

The oil phase in the emulsions of the invention may constitute 1 to 50%v/v of the emulsion. A preferred concentration of oil in the emulsion isfrom 10 to 40% v/v. Particularly preferred are concentrations of 20 to30% v/v.

The emulsion compositions of the invention can be prepared usingconventional methods such as by homogenisation of a mixture of the oiland analgesic component with an aqueous phase (optionally together witha stabilizing agent). Any suitable device may be used, including amicrofluidizer or ultrasonic device, though microfluidizers arepreferred for large scale production.

Suitable stabilizers for use in the emulsions of the invention includeblock copolymers containing a polyoxyethylene block (i.e. a block madeup of repeating ethylene oxide moieties). An example of a suitablestabilizer of this type is Poloxamer™. Other suitable stabilizersinclude phospholipid emulsifiers (for example soy and egg lecithins).Particularly preferred is the egg lecithin Lipoid E80™ (from Lipoid™),which contains both phosphatidylcholine and phosphatidyl ethanoline.Other suitable phospholipids include phospholipid-polyethylene glycol(PEG) conjugates (see for example Litzinger et al., Biochem BiophysActa, 1190 (1994) 99-107).

Any suitable concentration of stabilizer/emulsifier may be used, and ittypically falls within the range 0.1 to 10% w/v in the aqueous phase ofthe emulsion. Particularly preferred are concentrations of 1 to 5% w/v.

The stability of the emulsion can be enhanced by the addition of one ormore co-emulsifier(s). Suitable pharmaceutically-acceptableco-emulsifiers include fatty acids, bile acids and salts thereof.Preferred fatty acids have greater than 8 carbon atoms, and particularlypreferred is oleic acid. Of the suitable bile acids, preferred isdeoxycholic acid. Suitable salts of the foregoing include the alkalimetal (e.g. Na and K) salts. Co-emulsifiers can be added at aconcentration of 1% w/v or less on the aqueous phase.

Buffering agents may also be used in the composition. For example, abuffer may used to maintain a pH that is compatible with nasal fluid, topreserve emulsion stability and/or to ensure that the analgesiccomponent does not partition from the emulsion oil phase into theaqueous phase.

It will be clear to the person skilled in the art that additionalcomponents can also be added to the emulsion including thickening andgelling agents (such as cellulose polymers, particularly sodiumcarboxymethyl cellulose, alginates, gellans, pectins, acrylic polymers,agar-agar, gum tragacanth, gum xanthan, hydroxyethyl cellulose,chitosan, as well as block copolymers ofpolyoxyethylene-polyoxypropylene). Preservative agents such as methylparabenzoates, benzylalcohol and chlorobutanol may also be added.

The delivery agent may comprise a liposome. Liposomes are microscopicvesicles composed of an aqueous compartment surrounded by a phospholipidbilayer that acts as a permeable entrapment barrier. Many differentclasses of liposomes are known (see Gregoriadis (ed.) in LiposomeTechnology, 2nd edition, vol I-III, CRC Press, Boca Ranto, Fla., 1993).Some liposomes can provide controlled sustained release of theencapsulated drug. In such systems, the rate of drug release isdetermined by the liposome's physicochemical properties. Liposomes canbe tailored for a specific application by modification of size,composition, and surface charge to provide the desired rate of drugdelivery (see Meisner D, et al: In Proceedings, 15th InternationalSymposium on Controlled Release of Bioactive Materials. 15:262-263,1988; Mezei M: In Drug Permeation Enhancement, Theory and Application.Hsieh DS (ed.): Marcel Dekker Inc., New York, 1993, pp 171-198; andMeisner D, et al: J Microencapsulation 6:379-387, 1989). Thus,liposome-encapsulation can act as an effective and safe delivery agentin the compositions of the invention.

The sustained release property of the liposomal product can be regulatedby the nature of the lipid membrane and by the inclusion of otherexcipients in the composition of the liposomal products. Currentliposome technology permits a reasonable prediction on the rate of drugrelease based on the composition of the liposome formulation. The rateof drug release is primarily dependent on the nature of thephospholipids, e.g. hydrogenated (—H) or unhydrogenated (-G), or thephospholipid/cholesterol ratio (the higher this ratio, the faster therate of release), the hydrophilic/lipophilic properties of the activeingredients and by the method of liposome manufacturing.

Materials and procedures for forming liposomes are well known to thoseskilled in the art and include ethanol or ether injection methods.Typically, the lipid is dissolved in a solvent and the solventevaporated (often under reduced pressure) to produce a thin film. Thefilm is then hydrated with agitation. The analgesic component isincorporated at the lipid film forming stage (if lipophilic) or at thehydration phase as part of the aqueous hydrating phase (if hydrophilic).Depending on the hydration conditions selected and the physicochemicalproperties of the lipid(s) used, the liposomes can be multilamellarlipid vesicles (MLV), unilamellar lipid vesicles (including smallunilamellar vesicles (SUV) and large unilamellar vesicles (LUV)) and asmultivesicular liposomes.

Lipid components typically comprise phospholipids and cholesterol whileexcipients may comprise tocopherol, antioxidants, viscosity inducingagents and/or preservatives. Phospholipids are particularly useful, suchas those selected from the group consisting of phosphatidylcholines,lysophosphatidylcholines, phosphatidylserines,phosphatidylethanolamines, and phosphatidylinositols. Such phospholipidsmay be modified using, for example, cholesterols, stearylamines, stearicacid, and tocopherols.

The compositions of the invention may further comprise other suitableexcipients, including for example inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavouringagents, colouring agents and preservatives. Suitable inert diluentsinclude sodium and calcium carbonate, sodium and calcium phosphate, andlactose, while corn starch and alginic acid are suitable disintegratingagents. Binding agents may include starch and gelatin, while thelubricating agent, if present, will generally be magnesium stearate,stearic acid or talc.

Excipients such as humectants, isotonicity agents, antioxidants, buffersand/or preservatives are preferably used. Formulation and dosage willdepend on, amongst other things, whether the analgesic is to be used inthe form of drops or as a spray (aerosol). Alternatively, suspensions,ointments and gels can be applied to the nasal cavity. However, it isknown that nasal mucous membranes are also capable of toleratingslightly hypertonic solutions. Should a suspension or gel be desiredinstead of a solution, appropriate oily or gel vehicles may be used orone or more polymeric materials may be included, which desirably shouldbe capable of conferring bioadhesive characteristics to the vehicle.

Many other suitable pharmaceutically acceptable nasal carriers will beapparent to those skilled in the art. The choice of suitable carrierswill depend on the exact nature of the particular nasal dosage formdesired, for example whether the drug is to be formulated into a nasalsolution (for use as drops or as a spray), a nasal suspension, a nasalointment or a nasal gel. In another embodiment, nasal dosage forms aresolutions, suspensions and gels, which contain a major amount of water(preferably purified water) in addition to the active ingredient. Minoramounts of other ingredients such as pH adjusters (e.g. a base such asNaOH), emulsifiers or dispersing agents, buffering agents,preservatives, wetting agents and jelling agents (e.g., methylcellulose)may also be present.

When solutions, the nasal compositions of the invention may be isotonic,hypertonic or hypotonic. If desired, sustained release nasalcompositions, e.g. sustained release gels, can be readily prepared,preferably by employing the desired drug in one of its relativelyinsoluble forms, such as the free base or an insoluble salt.

The composition of the present invention may therefore be adjusted, ifnecessary, to approximately the same osmotic pressure as that of thebody fluids (i.e. isotonic). Hypertonic solutions can irritate thedelicate nasal membranes, while isotonic compositions do not.Isotonicity can be achieved by adding glycerol or an ionic compound tothe composition (for example, sodium chloride). The compositions maytake the form of a kit of parts, which kit may comprise the intranasalcomposition together with instructions for use and/or unit dosagecontainers and/or an intranasal delivery device.

The compositions of the invention are administered intranasally to apatient in order to induce analgesia. An effective amount of theanalgesic is delivered to a patient. A unit dose can be delivered to onenostril. Alternatively, half of a dose or two doses can be delivered toeach nostril each time administration occurs. The dose will depend upona number of factors including the analgesic that is being delivered, theage and sex of the patient, the nature and extent of the pain to betreated and the period of treatment. A suitable dose for an opioidanalgesic may be from 0.02 to 100 mg such as 0.1 to 50 mg. Forbuprenorphine or a buprenorphine salt or ester, a suitable dose is from0.02 to 1.2 mg, such as from 50 to 600 μg or from 100 to 400 μg,calculated as buprenorphine.

Multiple doses of a composition according to the invention may beemployed. For example, the rapid onset analgesia produced by thesolution of the invention may permit self-titration of analgesic by thepatient. The analgesic effect of an initial dose can be quickly andreliably gauged by the patient and, if insufficient, can be immediatelysupplemented by further dose(s) (often alternating between each nostril)until the required level of analgesia is attained. Multiple dosing mayalso be used in order to extend pain relief. For example, from 1 to 4doses, for example 2 to 4 doses, per day may be indicated.

The compositions of the invention may be used to treat an existing paincondition or to prevent a pain condition from occurring. An existingpain may be alleviated. Compositions can be used to treat or managechronic or acute pain, for example the management of post-operative pain(e.g. abdominal surgery, back surgery, cesarean section, hip replacementor knee replacement).

Other medical uses include: pre-operative intranasal administration ofthe solution of the invention; therapy or prophylaxis adjunctive toanesthesia; post-operative analgesia; the management of trauma pain; themanagement of cancer pain; the management of endometriosis; themanagement of inflammatory pain; the management of arthritis pain(including pain associated with rheumatoid arthritis andosteoarthritis); the management of back pain; the management ofmyocardial pain (for example ischaemic or infarction pain); theManagement of dental pain; the management of neuropathic pain (e.g.diabetic neuropathy, post-herpetic neuralgia or trigeminal neuralgia);the management of colic (e.g. renal colic or gallstones), headache,migraine, fibromyalgia or dysmenorrhoea; the management of breakthroughpain associated with malignant and non-malignant disease; and themanagement of acute procedural pain (e.g. bone marrow aspiration orlumber puncture).

When in the form of a solution, compositions according to the inventionmay be administered to the nasal cavity in forms including drops orsprays. The preferred method of administration is using a spray device.Spray devices can be single (unit) dose or multiple dose systems, forexample comprising a bottle, pump and actuator. Suitable spray devicesare available from various commercial sources including Pfeiffer,Valois, Bespak and Becton-Dickinson.

When in the form of powder or microspheres, a nasal insufflator devicemay be employed. Such devices are already in use for commercial powdersystems intended for nasal application. The insufflator may be used toproduce a fine, dispersed plume of the dry powder or microspheres. Theinsufflator is preferably provided with means for administering apredetermined dose of the analgesic composition. Powder or microspheresmay be contained in a bottle or container adapted to be used with theinsufflator. Alternatively, powders or microspheres may be provided incapsules (e.g. gelatin capsules) or other single dose devices adaptedfor nasal administration, in which embodiments the insufflator maycomprise means for breaking open the capsule (or other single dosedevice).

The invention also provides specific buprenorphine formulations whichare suitable for nasal delivery. A first solution of the inventionconsists essentially of 0.1 to 10 mg/ml of buprenorphine or aphysiologically acceptable salt or ester thereof, from 0.1 to 20 mg/mlof a chitosan, from 0.1 to 15 mg/ml of HPMC, and water. A secondsolution of the invention consists essentially of 0.1 to 10 mg/ml ofbuprenorphine or a physiologically acceptable salt or ester thereof,from 0.1 to 20 mg/ml of chitosan, from 50 to 200 mg/ml of apolyoxyethylene-polyoxypropylene copolymer of the general formulaHO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H wherein a is from 2 to 130 and b isfrom 15 to 67, and water.

In each case, the buprenorphine salt may be an acid addition salt or asalt with a base. Suitable acid addition salts the hydrochloride,sulphate, methane sulphonate, stearate, tartrate and lactate salts. Thehydrochloride salt is preferred.

The concentration of buprenorphine or buprenorphine salt or ester ineither solution is from 0.1 to 10 mg/ml, for example from 0.5 to 8mg/ml. Preferred concentrations are 1 to 6 mg/ml, for example 1 to 4mg/ml. Suitable solutions can contain the buprenorphine or buprenorphinesalt or ester at a concentration of 1 mg/ml or 4 mg/ml, calculated asbuprenorphine. Each solution is typically delivered as a nasal spray. A100 μl spray of a solution containing 1 to 4 mg/ml of buprenorphine or abuprenorphine salt or ester, calculated as buprenorphine, thus resultsin a clinical dose of 100 to 400 μg of the buprenorphine orbuprenorphine salt or ester, calculated as buprenorphine. Two suchsprays may be given per nostril per administration time to deliver adose of up to 4×400 μg, i.e. up to 1600 μg, of buprenorphine or thebuprenorphine salt or ester, calculated as buprenorphine.

Suitable chitosans are described above. The chitosan is present insolution at a concentration of from 0.1 to 20 mg/ml, for example from0.5 to 20 mg/ml. Preferably the solution contains from 1 to 15 mg/ml,more preferably from 2 to 10 mg/ml, of chitosan. A chitosanconcentration of 5 mg/ml is particularly suitable.

Any suitable HPMC may be employed, as described above also. The HPMCused in the solution of the invention is preferably one having anapparent viscosity (measured as a 2% solution in water at 20° C.) in therange from 3000 to 6000 cps. The concentration of the HPMC having aviscosity of from 3000 to 6000 cps is in the range from 0.1 to 15 mg/ml,preferably from 0.5 to 10 mg/ml and preferably from 1 to 5 mg/ml.

Suitable polyoxyethylene-polyoxypropylene copolymers typically aredescribed above. The polyoxyethylene-polyoxypropylene copolymer ispresent in an amount of from 50 to 200 mg/ml, preferably from 65 to 160mg/ml and more preferably from 80 to 120 mg/ml. A preferredconcentration is 100 mg/ml.

Any suitable preservative may be present in the solutions, in particulara preservative that prevents microbial spoilage of the solution. Thepreservative must be compatible with the other components of thesolution. The preservative may be any pharmaceutically acceptablepreservative, for example a quaternary ammonium compound such asbenzalkonium chloride.

The solution has a pH of from 3 to 4.8. Any pH within this range may beemployed provided the buprenorphine or buprenorphine salt or esterremains dissolved in the solution. The pH may be from 3.2 to 4.2, forexample from 3.2 to 4.0 or 3.5 to 4.0. A suitable pH is from 3.6 to 3.8.The pH may be adjusted to an appropriate value by addition of aphysiologically acceptable acid and/or physiologically acceptablebuffer. The pH may thus be adjusted solely by means of a physiologicallyacceptable mineral acid or solely by means of a physiologicallyacceptable organic acid. The use of hydrochloric acid is preferred.

A tonicity adjustment agent may be included in the solution. Thetonicity adjustment agent may be a sugar, for example dextrose, or apolyhydric alcohol, for example mannitol. A solution may be hypertonic,substantially isotonic or hypotonic. A substantially isotonic solutioncan have an osmolality of from 0.28 to 0.32 osmol/kg. An exactlyisotonic solution is 0.29 osmol/kg. A sufficient amount of a tonicityadjustment agent such as dextrose or mannitol may therefore be presentto achieve a desired osmolality. Preferably a solution contains 50 mg/mldextrose or mannitol.

The osmolality of a solution containing chitosan and HPMC or a poloxamermay be from 0.1 to 0.8 osmol/kg such as from 0.2 to 0.6 osmol/kg orpreferably from 0.32 to 0.4 osmol/kg.

The solutions may also contain other ingredients such as an antioxidant,chelating agent or other agent generally used in pharmaceutical liquidpreparations. The solution can be a sterile solution.

The solution containing chitosan and HPMC is prepared by dissolvingbuprenorphine or a physiologically acceptable salt or ester thereof, achitosan and HPMC in water, typically Water for Injections. The amountof the buprenorphine or salt or ester thereof is selected so that from0.1 to 10 mg/ml of buprenorphine or the buprenorphine salt or ester isdissolved in the solution. The required concentrations of the chitosanand of HPMC are provided too. A preservative can be dissolved in thesolution. The pH of the solution can be adjusted to a value within therange from 3 to 4.8 as required. Preferably the pH is adjusted by meansof hydrochloric acid.

A solution containing chitosan and a polyoxyethylene-polyoxypropylenecopolymer is prepared by dissolving buprenorphine or a physiologicallyacceptable salt or ester thereof, a chitosan and thepolyoxyethylene-polyoxypropylene copolymer in water, typically Water forInjections. The amount of the buprenorphine or salt or ester thereof isselected so that from 0.1 to 10 mg/ml of buprenorphine or thebuprenorphine salt or ester is dissolved in the solution. The requiredconcentrations of the chitosan and of thepolyoxyethylene-polyoxypropylene copolymer are provided too. Apreservative can be dissolved in the solution. The pH of the solutioncan be adjusted to a value within the range from 3 to 4.8 as required.Preferably, the pH is adjusted by means of hydrochloric acid.

Other components can be provided in the solutions at any convenientstage. For example, dextrose or mannitol may be dissolved in the waterin which the buprenorphine or buprenorphine salt or ester is beingdissolved. A sterile solution can be obtained either by using sterilestarting materials and operating under sterile conditions and/or byusing standard sterilising techniques such as passing the final solutionthrough a sterilising filter. A pyrogen-free solution can thus beprovided. The solution can then be introduced into a nasal deliverydevice, typically a sterile such device. If required, prior to sealingthe device, the solution may be overlaid with an inert gas such asnitrogen to protect it from oxidation.

A third pharmaceutical solution of the invention consists essentially of0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable salt orester thereof, from 5 to 40 mg/ml of a pectin having a low degree ofesterification, in particular a degree of esterification of less than50%, and water. The buprenorphine salt may be an acid addition salt or asalt with a base. Suitable acid addition salts include thehydrochloride, sulphate, methane sulphonate, stearate, tartrate andlactate salts. The hydrochloride salt is preferred.

The concentration of buprenorphine or buprenorphine salt or ester isfrom 0.1 to 10 mg/ml, for example from 0.5 to 8 mg/ml. Preferredconcentrations are 1 to 6 mg/ml, for example 1 to 4 mg/ml calculated asbuprenorphine. Suitable solutions can contain buprenorphine or abuprenorphine salt or ester in an amount of 1 mg/ml or 4 mg/ml,calculated as buprenorphine.

The solution is typically delivered as a nasal spray. A 100 μl spray ofa solution containing 1 to 4 mg/ml of buprenorphine or a buprenorphinesalt or ester, calculated as buprenorphine thus results in a clinicaldose of 100 to 400 μg of the buprenorphine or buprenorphine salt orester, calculated as buprenorphine. Two such sprays may be given pernostril per administration time to deliver a dose of up to 4×400 μg,i.e. up to 1600 μg, of buprenorphine or the buprenorphine salt or ester,calculated as buprenorphine.

Suitable pectins for inclusion in the solution are described above. Thesolutions gels on the mucosal surfaces of the nasal cavity without theneed for extraneous source of divalent metal ions. The pectin is presentin the solution of the invention at a concentration of from 5 to 40mg/ml, for example from 5 to 30 mg/ml. More preferably, the pectinconcentration is from 10 to 30 mg/ml or from 10 to 25 mg/ml.

A pectin-containing solution of the invention has a pH of from 3 to 4.2.Any pH within this range may be employed provided the buprenorphine orbuprenorphine salt or esteremains dissolved in the solution. The pH maybe from 3.2 to 4.0, for example from 3.5 to 4.0. A particularly suitablepH is from 3.6 to 3.8. The pH may be adjusted to an appropriate value byaddition of a physiologically acceptable acid and/or physiologicallyacceptable buffer. The pH may thus be adjusted solely by means of aphysiologically acceptable mineral acid or solely by means of aphysiologically acceptable organic acid. The use of hydrochloric acid ispreferred.

Any suitable preservative may be present in the pectin-containingsolution, in particular a preservative that prevents microbial spoilageof the solution. The preservative may be any pharmaceutically acceptablepreservative, for example phenylethyl alcohol or propyl hydroxybenzoate(propylparaben) or one of its salts. The phenylethyl alcohol and thepropylparaben or propylparaben salt are preferably used in combination.The preservative must be compatible with the other components of thesolution and, in particular, must not cause gelling of the solution.

Pectin-containing solutions may include a tonicity adjustment agent suchas a sugar, for example dextrose, or a polyhydric alcohol for examplemannitol. A solution may be hypertonic, substantially isotonic orhypotonic. A substantially isotonic solution can have an osmolality offrom 0.28 to 0.32 osmol/kg. An exactly isotonic solution is 0.29osmol/kg. The osmolality of a solution may be from 0.1 to 0.8 osmol/kgsuch as from 0.2 to 0.6 osmol/kg or preferably from 0.35 to 0.5osmol/kg. A suitable osmolality range is from 0.32 to 0.36 osmol/kg. Asufficient amount of a tonicity adjustment agent such as dextrose ormannitol may therefore be present to achieve such osmolalities.Preferably a solution contains 50 mg/ml dextrose or mannitol.

The pectin-containing solution is prepared by dissolving buprenorphineor a physiologically acceptable salt or ester thereof in water,typically Water for Injections, and the resulting solution is mixed witha solution of a suitable pectin in water, again typically Water forInjections. The amount of the buprenorphine or salt or ester thereof andof the pectin are selected so that from 0.1 to 10 mg/ml of buprenorphineor the buprenorphine salt or ester and from 5 to 40 mg/ml of pectin aredissolved in the mixed solution. A preservative or combination ofpreservatives may be dissolved in the solution. The pH of the mixed,solution can be adjusted to a value within the range from 3 to 4.2 asrequired. Preferably, the pH is adjusted with hydrochloric acid if pHadjustment is required.

Other components can be provided in solution at any convenient stage.For example, dextrose or mannitol may be dissolved in the water in whichthe buprenorphine or buprenorphine salt or ester is being dissolved. Asterile solution can be obtained either by using sterile startingmaterials and operating under sterile conditions and/or by usingstandard sterilising techniques such as passing the final solutionthrough a sterilising filter. A pyrogen-free solution can thus beprovided. The solution can then be introduced into a nasal deliverydevice, typically a sterile such device. If required, prior to sealingthe device, the solution may be overlaid with an inert gas such asnitrogen to protect it from oxidation.

Each of the three solutions of the invention is administeredintranasally to a patient in order to induce analgesia. Rapid onset ofanalgesia and prolonged analgesia can thus be obtained. An effectiveamount of buprenorphine or a salt or ester thereof is delivered to apatient. A unit dose can be delivered to one nostril. Alternatively,half of a dose or two doses can be delivered to each nostril eachadministration time. The dose will depend upon a number of factorsincluding the age and sex of the patient, the nature and extent of thepain to be treated and the period of treatment. A suitable dose ofbuprenorphine or a buprenorphine salt or ester is from 0.02 to 1.2 mg,such as from 50 to 600 μg or from 100 to 400 μg, calculated asbuprenorphine.

Multiple doses of a solution according to the invention may be employed.For example, the rapid onset analgesia produced by the solution of theinvention may permit self-titration of analgesic by the patient. Theanalgesic effect of an initial dose can be quickly and reliably gaugedby the patient and, if insufficient, can be immediately supplemented byfurther dose(s) (often alternating between each nostril) until therequired level of analgesia is attained. Multiple dosing may also beused in order to extend pain relief For example, from 2 to 4 doses perday may be indicated.

The solutions of the invention may be used to treat an existing paincondition or to prevent a pain condition from occurring. An existingpain may be alleviated. Solutions of the invention can be used to treator manage chronic or acute pain, for example the management ofpost-operative pain (e.g. abdominal surgery, back surgery, cesareansection, hip replacement or knee replacement). Other medical uses havebeen described above.

The solutions according to the invention may be administered to thenasal cavity in forms including drops or sprays. The preferred method ofadministration is using a spray device. Spray devices can be single(unit) dose or multiple dose systems, for example comprising a bottle,pump and actuator. Suitable spray devices are available from variouscommercial sources including Pfeiffer, Valois, Bespak andBecton-Dickinson.

As already mentioned, rapid onset of analgesia and prolonged analgesiacan be achieved by means of the invention. The analgesic deliveryprofile that can be attained may avoid the relatively high C_(max)values associated with intravenous administration and so lead to animproved therapeutic index. The peak plasma concentration of ananalgesic that is attained after administration is defined as C_(max).The invention can permit reduction or elimination of some or all of theside effects associated with the analgesic.

C_(max) is typically from 1 to 5 ng/ml, for example from 1 to 4 ng/ml orfrom 1.5 to 3 ng/ml. C_(max) may be from 1 to 2 ng/ml, especially forlower doses of buprenorphine. The time at which C_(max) is reached(T_(max)) is typically 10 to 40 minutes after administration, forexample 10 to 30 minutes or 15 to 25 minutes such as 15 to 20 minutes.

In preferred embodiments, the delivery agent is adapted to deliver theanalgesic component such that C_(max)=C_(opt). The term C_(opt) is usedin relation to analgesic drugs which exhibit a dose-response curve toanalgesia which is displaced to the left with respect to thedose-response curve for side-effects. The term defines a therapeuticplasma concentration or range thereof which produces acceptable painrelief or pain amelioration but which does not produce side-effects orproduces side effects which are less than those associated with higherplasma concentrations.

Preferably, the solutions of the invention enable the buprenorphine orsalt or ester thereof to be delivered such that a C_(ther) of 0.2 ng/mlor more, for example 0.4 ng/ml or more, is attained within 30 minutesafter introduction into the nasal cavity within 30 minutes, for examplewithin 0.5 to 20 minutes, such as 2 to 15 minutes or 5 to 10 minutes.The term C_(ther) defines a therapeutic plasma concentration (or rangethereof). Thus, the term is used herein to define a blood plasmaconcentration (or range of plasma concentrations) of the buprenorphineor salt or ester thereof that produces pain relief or pain amelioration.C_(ther) may be from 0.4 to 5 ng/ml, for example 0.4 to 1 ng/ml or 0.5to 4 ng/ml or 0.8 to 2 ng/ml.

The T_(maint) is typically at least 2 hours. The term T_(maint) definesthe duration of maintenance of C_(ther) after administration of theanalgesic. For example, the T_(maint) can be from up to 24 hours, up to12 hours or up to 6 hours such as from 2 to 4 hours or 2 to 3 hours. Bymeans of the invention, therefore, a C_(ther) of at least 0.4 ng/ml maybe attained within 2 to 15 minutes and maintained for a time periodT_(maint) of from 2 to 4 hours.

The following Examples illustrate the invention.

Example 1 Nasal Solution Containing Buprenorphine (4 mg/ml) and Pectin

5 g of pectin (SLENDID (trade mark) 100, CP Kelco, Denmark) wasdissolved by stirring into approximately 180 ml of water for injection(WFI) (Baxter, UK). 1075 mg of buprenorphine hydrochloride (MacFarlanSmith, UK) and 12.5 g of dextrose (Roquette) were dissolved into thepectin solution. 1:25 ml of phenylethyl alcohol (R. C. Treat, UK) and 50mg of propyl hydroxybenzoate (Nipa, UK) were dissolved into thepectin/buprenorphine solution. The solution was adjusted to 250 ml usingWFI. 1M hydrochloric acid (BDH, UK) was added to adjust the pH to 3.6.

The final product was a slightly turbid solution 4.3 mg/ml buprenorphinehydrochloride (corresponding to 4 mg/ml buprenorphine), 20 mg/ml pectin,50 mg/ml dextrose, 5 μl/ml phenylethyl alcohol and 0.2 mg/ml propylhydroxybenzoate. The pH of the solution was 3.6, as mentioned above. Theosmolality of the solution was 0.46 osmol/kg.

Single dose nasal spray devices (Pfeiffer, Germany) were filled with thesolution. Each device was filled with 123 μl of liquid. Actuation of thedevice delivered a dose of 100 μl of liquid containing 400 μg ofbuprenorphine and 2 mg of pectin.

Example 2 Nasal Solution Containing Buprenorphine (2 mg/ml) and Pectin

5 g of pectin is dissolved by stirring into approximately 180 ml of WFI.538 mg of buprenorphine hydrochloride and 12.5 g of dextrose aredissolved into the pectin solution. 1.25 ml of phenylethyl alcohol and50 mg of propyl hydroxybenzoate are dissolved into thepectin/buprenorphine solution. The solution is adjusted to 250 ml usingWFI.

The final product is a slightly turbid solution containing 2.16 mg/mlbuprenorphine hydrochloride (corresponding to 2 mg/ml buprenorphine), 20mg/ml pectin, 50 mg/ml dextrose, 5 μl/ml phenylethyl alcohol and 0.2mg/ml propyl hydroxybenzoate.

123 μl of the above solution is filled into a Valois Monospray singledose nasal spray device (Pfeiffer, Germany). Actuation of the devicewill deliver a dose of 100 μl of liquid containing 200 μg ofbuprenorphine and 2 mg of pectin.

Example 3 Nasal Solution Containing Buprenorphine (4 mg/ml), Chitosanand HPMC

0.75 g of HPMC (Methocel (trade mark) E4M, Colorcon, UK) was dispersedinto approximately 125 ml of pre-heated (70-80° C.) water for injection(WFI) (Baxter, UK). The HPMC dispersion was stirred in an ice bath untila clear solution had formed. 1.25 g of chitosan glutamate (Protosan(trade mark) UPG213, Pronova, Norway) was dissolved in the HPMCsolution. 75 mg of 50% w/w benzalkonium chloride solution (Albright andWilson, UK) was dispersed in 10 ml of WFI and transferred with anadditional 40 ml of WFI to a 250 ml volumetric flask. 1075 mg ofbuprenorphine hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose(Roquette, UK) were transferred into the volumetric flask. Thechitosan/HPMC solution and an additional 40 ml of WFI were added to theflask. The solution was adjusted to pH 3.4 using 1M hydrochloric acidsolution (BDH, UK) and the flask contents adjusted to 250 ml using WFI.

The final product was a clear colourless solution containing a 4.3 mg/mlbuprenophine hydrochloride (corresponding to 4 mg/ml buprenorphine), 5mg/ml chitosan glutamate, 3 mg/ml HPMC, 50 mg/ml dextrose and 0.15 mg/mlbenzalkonium chloride. The osmolality of the final solution was 0.34osmol/kg and the viscosity, as measured using a Brookfield CP70 cone andplate viscometer was 84.7 cps at 2.5 rpm and 25° C.

Single dose nasal spray devices (Pfeiffer, Germany) were filled with thesolution. Each device was filled with 123 μl of liquid. Actuation of thedevice delivered a dose of 100 μl of liquid containing 400 μg ofbuprenorphine, 0.5 mg of chitosan and 0.3 mg of HPMC. Hence, a dose of400 μg buprenorphine is provided by a single spray into one nostril. Adose of 800 μg is provided by a single spray into each nostril.

Example 4 Nasal Solution Containing Buprenorphine (1 mg/ml), Chitosanand HPMC

A solution containing HPMC, chitosan glutamate and benzalkonium chlorideis prepared according to Example 3. 269 mg of buprenorphinehydrochloride and 12.5 g of mannitol (Sigma, UK) are transferred intothe volumetric flask. The chitosan/HPMC solution and an additional 40 mlof WFI are added to the flask. The pH of the solution is adjusted to pH3.6 using 1M hydrochloric acid solution and the flask contents adjustedto 250 ml using WFI.

The final product is a clear colourless solution containing 1.08 mg/mlbuprenorphine hydrochloride (corresponding to 1 mg/ml buprenorphine), 5mg/ml chitosan glutamate, 3 mg/ml HPMC, 50 mg/ml mannitol and 0.15 mg/mlbenzalkonium chloride.

123 μl of the above solution is filled into a single dose nasal spraydevice (Pfeiffer, Germany). Actuation of the device will deliver a doseof 100 μl of liquid containing 100 μg of buprenorphine, 0.5 mg ofchitosan and 0.3 mg of HPMC.

5 ml of the solution is filled into a 10 ml glass bottle. A Valois VP7,100 μl pump and actuator (Valois, France) are attached to the bottle.When primed, the pump will dispense 100 μl of solution containing 100 μgof buprenorphine.

Example 5 Nasal Solution Containing Buprenorphine (4 mg/ml), Chitosanand Poloxamer

25 g of poloxamer 188 (Lutrol (trade mark) F-68, BASF, Germany) wasdissolved by stirring into 100 ml of water for injection (WFI) (Baxter,UK) at a temperature of 2 to 8° C. 1.25 g of chitosan glutamate(Protasan (trade mark) UPG213, Pronova, Norway) was dissolved in thepoloxamer solution. 75 mg of 50% w/w benzalkonium chloride solution(Albright and Wilson, UK) was dispersed in 10 ml of WFI and transferredwith an additional 40 ml of WFI to a 250 ml volumetric flask. 1075 mg ofbuprenorphine hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose(Roquette, UK) were transferred into the volumetric flask. Thechitosan/poloxamer solution and an additional 40 ml of WFI were added tothe flask. The solution was adjusted to pH 3.4 using 1M hydrochloricacid solution (BDH, and the flask contents adjusted to 250 ml using WFI.

The final product was a clear colourless solution containing 4.3 mg/mlbuprenorphine hydrochloride (corresponding to 4 mg/ml buprenorphine), 5mg/ml chitosan glutamate, 100 mg/ml poloxamer 188, 50 mg/ml dextrose and0.15 mg/ml benzalkonium chloride. The osmolality of the final solutionwas 0.60 Osmol/kg.

Single dose nasal spray devices (Pfeiffer, Germany) were filled with thesolution. Each device was filled with 123 μl of liquid. Actuation of thedevice delivered a dose of 100 μl of liquid containing 400 μg ofbuprenorphine, 0.5 mg of chitosan and 10 mg of poloxamer 188.

Example 6 Nasal Solution Containing Buprenorphine (1 mg/ml), Chitosanand Poloxamer

A solution containing chitosan glutamate, poloxamer 188 and benzalkoniumchloride is prepared according to Example 5. 269 mg of buprenorphinehydrochloride and 12.5 g mannitol (Sigma, UK) are transferred into thevolumetric flask. The chitosan/poloxamer solution and an additional 40ml of WFI are added to the flask. The pH of the solution is adjusted topH 3.6 using 1M hydrochloric acid and the flask contents adjusted to 250ml using WFI.

The final product is a clear colourless solution containing 1.08 mg/mlbuprenorphine hydrochloride (corresponding to 1 mg/ml buprenorphine), 5mg/ml chitosan glutamate, 100 mg/ml poloxamer 188, 50 mg/ml mannitol and0.15 mg/ml benzalkonium chloride.

123 μl of the above solution is filled into a single dose nasal spraydevice (Pfeiffer, Germany). Actuation of the device will deliver a doseof 100 μl of liquid containing 100 μg of buprenorphine, 0.5 mg ofchitosan and 10 mg of poloxamer 188.

4 ml of the solution is filled into a 5 ml glass bottle. A Pfeiffer 100μl nasal spray pump and actuator are attached to the bottle. Whenprimed, the pump will dispense 100 μl of solution containing 100 μg ofbuprenorphine.

Example 7 Effects of Varying Parameters of Buprenorphine-PectinSolutions General Methods

The appearance, pH (Mettler MP230 pH meter) and osmolality (Osmomat 030cryoscopic osmometer) of the solutions were determined.

The viscosity of the solution was measured using a Brookfield Cone andPlate Rheometer. Results given are the mean of determinations at threerotation speeds appropriate to the viscosity of the solution.

The spray characteristics from a Pfeiffer multi-dose nasal spray device(standard nozzle, 0.1 ml pump, Cat. No. 62897) were evaluated bymeasurement of plume angle using image analysis. Results given are themean of four determinations (two at one orientation and two at a 90°rotation to the first orientation).

The buprenorphine content of formulations was determined by hplc.

Gels were prepared by controlled mixing of 20 ml of formulation with 5ml of a standard calcium chloride solution (9.44 mg/ml CaCl₂.2H₂0)before standing for 1 hour at room temperature. A visual assessment ofthe structure, uniformity, clarity and evidence of syneresis of each gelwas conducted and, in addition, the gel structure was examined with aStable Microsystems Texture Analyser. Results (from singledeterminations) are expressed in terms of force (maximum penetrationforce) and area (total work of gel penetration).

Effect of Pectin Concentration on Appearance, Solution/Gel Propertiesand Spray Characteristics 1. Methods

Buprenorphine hydrochloride (107.5 mg) and anhydrous dextrose (1.25 g)were stirred in 18-20 ml water in a 25 ml volumetric flask together withan appropriate quantity of pectin and the mixture stirred overnight oruntil a solution formed. The mixture was then made up to 25 ml withwater to give a solution containing 4 mg/ml buprenorphine, 50 mg/mldextrose and 1, 5, 10, 20, 30, 40 or 80 mg/ml pectin and the pH,appearance, osmolality, viscosity were determined. In addition, spraycharacteristics from a Pfeiffer multi-dose nasal spray device (standardnozzle, 0.1 ml pump, Cat. No. 62897) were evaluated by measurement ofplume angle using image analysis. Gels were prepared by controlledmixing of 20 ml of formulation with 5 ml of a standard calcium chloridesolution (9.44 mg/ml CaCl₂.2H₂0) before standing for 1 hour at roomtemperature. A visual assessment of the structure, uniformity, clarityand evidence of syneresis of each gel was conducted and, in addition,the gel structure was examined with a Stable Microsystems TextureAnalyser.

An in vitro method was employed to simulate the gelling that may occurwhen the pectin formulation comes into contact with the nasal mucosalsurface. This involved adding 2 ml of each formulation to an equalvolume of simulated nasal electrolyte solution (SNES) (comprised 8.77g/l sodium chloride, 2.98 g/l potassium chloride and 0.59 g/l calciumchloride dihydrate) and agitating gently. The mixtures were left tostand for 1 hour at room temperature before visual assessment.

2. Results

As pectin concentration increased, solutions became increasingly turbid,osmolality and viscosity increased and plume angle decreased (Table 1).An excellent relationship was obtained between concentration and plumeangle up to 30 mg/ml pectin. The pH was not significantly affected bypectin concentration.

Upon addition of calcium ions pectin formed visually satisfactory gelsin the concentration range 5-20 mg/ml (Table 2). Correspondingly greaterintegrity of gel structure was noted over this range. At higher pectinconcentrations texture analysis results were inconclusive becausehomogeneity of the gel is difficult to control and increasing syneresiswas observed.

At a lower calcium ion concentration (SNES) pectin produced mobile gelsat 10-20 mg/ml and strong, inhomogeneous gels at higher concentrations.

TABLE 1 Appearance, pH, osmolality, viscosity and spray characteristics(plume angle) of buprenorphine solutions containing 4.3 mg/mlbuprenorphine hydrochloride (BPN•HCl), 50 mg/ml dextrose and differentconcentrations of pectin (Slendid 100). Pectin Osmo- Vis- Plume BatchConc. lality cosity angle No. (mg/ml) pH (osmol/kg) (cps) (°) Appearance105 1 4.4 0.32 1.4 56 Clear, colourless solution 106 5 4.2 0.33 2.1 53Very slightly turbid, colourless solution 107 10 4.1 0.34 3.7 42Slightly turbid, colourless solution 108 20 4.0 0.37 9.0 29 Slightlyturbid, pale yellow solution 153 30 3.9 0.40 16.8 21 Turbid, pale yellowsolution 109 40 4.0 0.43 33.9 20 Turbid, pale yellow solution 110 80 4.00.55 N/M* 16 Very turbid, pale yellow solution *N/M = not measurable

TABLE 2 Gelling properties of buprenorphine solutions containing 4.3mg/ml BPN•HCl, 50 mg/ml dextrose and different concentrations of pectin(Slendid 100) when mixed with a standard calcium chloride solution.Pectin Texture analysis Batch Conc. Force Area No. (mg/ml) (g) (g s)Visual assessment 105 1 — — Clear, slightly viscous, colourlesssolution. Did not gel. 106 5 116 1420 Slightly opalescent, strong,uniform gel with minimum syneresis. 107 10 220 3858 Semi-transparent,strong, uniform gel with minimum syneresis. 108 20 279 4872Semi-transparent, pale yellow, strong, uniform gel with minimumsyneresis. 153 30 190 4259 Semi-transparent, pale yellow, strong,uniform gel with some syneresis. 109 40 234 2691 Semi-transparent, paleyellow, very strong, non-uniform gel with some syneresis. 110 80 3035356 Semi-transparent, yellow, extremely strong, non-uniform gel withsignificant syneresis.

TABLE 2a Gelling properties of buprenorphine solutions containing 4.3mg/ml BPN•HCl, 50 mg/ml dextrose and different concentrations of pectin(Slendid 100) when mixed with SNES. Pectin Batch Conc. No. (mg/ml)Visual assessment 161 1 Clear, slightly viscous, colourless solution.Did not gel. 162 5 Clear, viscous, colourless solution. Did not gel. 16310 Clear, colourless, weak diffuse gel. 164 20 Pale yellow,semi-transparent weak diffuse gel. 165 30 Semi-transparent pale yellow,strong gel with some syneresis. 166 40 Semi-transparent pale yellow,strong gel with some syneresis. 167 80 Opaque pale yellow, very stronggel with significant syneresis.

Effect of pH on Solubility and Gelling Properties of BuprenorphineHydrochloride 1. Methods

Stock solutions containing pectin (Slendid 100) (20 mg/ml) and dextrose(50 mg/ml) were prepared at various pH in the range pH 3.0 to 6.0 (pHadjustments were made with 0.1M HCl or 0.1M meglumine). An excess ofbuprenorphine hydrochloride was then stirred overnight at 18° C. in 5 or25 ml of each solution. Saturated solutions were recovered by passingeach mixture through a 0.2 μm polycarbonate membrane filter. Theconcentration of buprenorphine hydrochloride in the filtrate wasdetermined by hplc.

In preliminary experiments addition of excess buprenorphinehydrochloride was found to reduce the pH of the (unbuffered) solutions.In order to produce solutions at the higher end of the desired pH range,a minimal excess of buprenorphine hydrochloride was added to solutions(5 ml) containing pectin (Slendid 100) 20 mg/ml) and dextrose (50 mg/ml)adjusted to various pH values in the range pH 4.5 to 6.0 with 0.1M HClor 0.1M meglumine. The quantity of excess buprenorphine hydrochlorideadded was based on preliminary findings and on reported solubility datafor buprenorphine hydrochloride (Cassidy et al, J. Controlled Release25, 21-29, 1993). Following overnight stirring at 18° C., mixtures wereexamined to confirm that undissolved drug remained before saturatedsolutions were recovered by passing each mixture through a 0.2 μmpolycarbonate membrane filter.

For selected formulations gels were prepared by controlled mixing of 20ml of formulation with 5 ml of a standard calcium chloride solution(9.44 mg/ml CaCl₂.2H₂O) before standing for 1 hour at room temperature.A visual assessment of the structure, uniformity, clarity and evidenceof syneresis of each gel was conducted and, in addition, the gelstructure was examined with a Stable Microsystems Texture Analyser.

2. Results

Buprenorphine was sparingly soluble (greater than 10 ng/ml) in aqueoussolutions containing 20 mg/ml pectin+50 mg/ml dextrose at pH below 4.4(Table 3). In general, solubility fell as pH increased above 4.5 (Table3a). Solutions were slightly soluble (less than 10 ng/ml) at pH 4.5-6.0.

Gelling properties were largely unaffected by pH (and therefore bybuprenorphine concentration) (Table 4).

TABLE 3 Solubility of BPN•HCl at pH 3.2-4.0 in solutions containing 20mg/ml pectin (Slendid 100) and 50 mg/ml dextrose. Buprenorphine BatchNo. Final pH detected* (mg/ml) 043 3.2 12.3 085 3.6 14.2 086 3.8 13.5087 3.9 15.8 048 4.0 14.3 *Expressed as buprenorphine free base

TABLE 3a Solubility of BPN•HCl at pH 4.4-5.3 in solutions containing 20mg/ml pectin (Slendid 100) and 50 mg/ml dextrose. Buprenorphine BatchNo. Final pH detected* (mg/ml) 202 4.4 11.6 203 4.5 9.0 204 4.7 7.3 2054.7 6.0 206 4.8 3.5 207 5.1 2.7 209 5.2 1.4 208 5.3 1.3 *Expressed asbuprenorphine free base

TABLE 4 Effect of pH on the gelling properties of BPN•HCl in solutioncontaining 20 mg/ml pectin (Slendid 100) and 50 mg/ml dextrose whenmixed with a standard calcium chloride solution. Texture analysis* BatchpH Force Area No. (actual) (g) (g s) Visual assessment 043 3.0 (3.2) 3284439 Semi-transparent, uniform gel with minimum syneresis. 086 3.5 (3.8)309 4018 Semi-transparent, uniform gel with minimum syneresis. 048 4.0(3.9) 371 4056 Semi-transparent, uniform gel with minimum syneresis. 0895.5 (5.1) 168 1620 Semi-transparent, uniform gel with some syneresis.*Reduced volumes (14 ml of formulation and 3.5 ml of CaCl₂•2H₂O) wereused due to higher than expected loss of volume during filtration.

Effect of Osmolality (Dextrose or Mannitol Concentration) on Viscosity,Spray Characteristics and Gelling Properties of BuprenorphineHydrochloride 1. Methods

Buprenorphine hydrochloride (107.5 mg) and pectin (Slendid 100) (500 mg)were stirred in 18-20 ml water in a 25 ml volumetric flask together withan appropriate quantity of anhydrous dextrose or mannitol and themixture stirred overnight or until a solution formed. The mixture wasthen made up to 25 ml with water to give a solution containing 4 mg/mlbuprenorphine, 20 mg/ml pectin and 15, 50, 87, 122, 157 or 192 mg/mldextrose (or 15, 50, 87, 122 mg/ml mannitol) and the pH, appearance,osmolality, viscosity were determined. In addition, spraycharacteristics from a Pfeiffer multi-dose nasal spray device (standardnozzle, 0.1 ml pump, Cat. No. 62897) were evaluated by measurement ofplume angle using image analysis. Gels were prepared by controlledmixing of 20 ml of formulation with 5 ml of a standard calcium chloridesolution (9.44 mg/ml CaCl₂.2H₂0) before standing for 1 hour at roomtemperature. A visual assessment of the structure, uniformity, clarityand evidence of syneresis of each gel was conducted and, in addition,the gel structure was examined with a Stable Microsystems TextureAnalyser.

2. Results

As dextrose concentration increased from 15 to 50 mg/ml spraycharacteristics from a nasal spray device were affected as indicated bya decrease in plume angle associated with an increase in viscosity: anarrow plume was consistently obtained above 50 mg/ml dextrose (Table5). As mannitol concentration increased there was a slight increase inviscosity and a slight decrease in plume angle (Table 6).

Gel structure may have been slightly weakened as dextrose concentrationincreased. This was indicated by a visual assessment but textureanalysis results were inconclusive (Table 7).

Gel structure was affected at higher mannitol concentration. Visualassessment and texture analysis indicated that less uniform and weakergels were produced (Table 8).

TABLE 5 Osmolality, viscosity and spray characteristics of 4.3 mg/mlBPN•HCl/20 mg/ml pectin (Slendid 100) solution containing varyingconcentrations of dextrose. Dextrose Batch concentration OsmolalityViscosity Plume No. (mg/ml) (osmol/kg) (cps) angle (°) 114 15 0.15 8.043 115 50 0.37 9.2 30 116 87 0.62 10.3 22 117 122 0.88 11.5 19 118 1571.18 13.0 23 119 192 1.5 14.5 17

TABLE 6 Osmolality, viscosity and spray characteristics of 4.3 mg/mlBPN•HCl/20 mg/ml pectin (Slendid 100) solution containing varyingconcentrations of mannitol. Batch Mannitol conc. Osmolality ViscosityPlume No. (mg/ml) (osmol/kg) (cps) angle (°) 120 15 0.16 8.4 33 121 500.37 9.2 22 122 87 0.61 10.3 22 123 122  0.85 11.3 21 124 157* — — — 125192* — — — *Did not dissolve

TABLE 7 Gelling properties of 4.3 mg/ml BPN•HCl/20 mg/ml pectin (Slendid100) solution containing varying concentrations of dextrose. Textureanalysis Batch Osmolality Force Area No. (osmol/kg) (g) (g s) Visualassessment 114 0.15 574 10338 Very strong, uniform, semi- transparentpale yellow gel with minimum syneresis. 115 0.37 359 6589 Very strong,uniform, semi- transparent pale yellow gel with minimum syneresis. 1160.62 280 5520 Strong, uniform, semi- transparent pale yellow gel withminimum syneresis. 117 0.88 336 5019 Strong, uniform, semi- transparentpale yellow gel with minimum syneresis. 118 1.18 467 7066 Strong,uniform, semi- transparent pale yellow gel with minimum syneresis. 1191.5 249 3435 Strong, uniform, semi- transparent pale yellow gel withsome syneresis.

TABLE 8 Gelling properties of 4.3 mg/ml BPN•HCl/20 mg/ml pectin (Slendid100) solution containing varying concentrations of mannitol when mixedwith a standard calcium chloride solution. Texture analysis BatchOsmolality Force Area No. (osmol/kg) (g) (g s) Visual assessment 1200.16 477 9006 Strong, uniform, semi- transparent pale yellow gel withsome syneresis. 121 0.37 497 8991 Strong, uniform, semi- transparentpale yellow gel with some syneresis. 122 0.61 358 7160 Weak,non-uniform, semi- transparent pale yellow gel with some syneresis 1230.85 221 3881 Weak, non-uniform, semi- transparent pale yellow gel withsome syneresis

Effect of Dextrose and Mannitol Concentration on BuprenorphineSolubility 1. Methods

Solutions containing pectin (Slendid 100) (20 mg/ml) were prepared at pH3, 4, 5 and 6 (pH adjustments were made with 0.1M HCl or 0.1Mmeglumine). Into 5 ml of each solution was dissolved 0, 62.5, 125, 187.5or 200 mg anhydrous dextrose or mannitol to give approximatedextrose/mannitol concentrations of 0, 12.5, 25, 37.5 or 50 mg/mlrespectively. An excess of buprenorphine hydrochloride was then addedand the mixture stirred overnight at 18° C. Saturated buprenorphinehydrochloride solutions were produced by passing each mixture through a0.2 μm polycarbonate membrane filter. The concentration of buprenorphinehydrochloride in the filtrate was determined by hplc.

2. Results

Buprenorphine solubility in aqueous solution containing 20 mg/ml pectinwas not affected significantly by dextrose (Table 9) or mannitol (Table10) concentration across the measured pH range.

TABLE 9 Effect of dextrose concentration on the solubility of BPN•HCl insolution containing 20 mg/ml pectin (Slendid 100). DextroseBuprenorphine concentration pH detected* Batch No. (mg/ml) (actual)(mg/ml) 036 0 3 (3.1) 13.7 040 12.5 3 (2.9) 13.1 041 25 3 (2.7) 13.9 04237.5 3 (3.0) 13.9 043 50 3 (3.2) 12.3 037 0 4 (3.9) 16.4 045 12.5 4(3.8) 16.0 046 25 4 (3.9) 15.6 047 37.5 4 (4.0) 15.6 048 50 4 (4.0) 14.3038 0 5 (4.9) 4.4 050 12.5 5 (5.0) 5.7 051 25 5 (5.0) 4.4 052 37.5 5(5.1) 4.4 053 50 5 (5.2) 4.6 039 0 6 (5.9) 1.8 055 12.5 6 (5.7) 1.6 05625 6 (5.8) 1.7 057 37.5 6 (5.7) 1.7 058 50 6 (5.6) 1.8 *Expressed asbuprenorphine free base

TABLE 10 Effect of mannitol concentration on the solubility of BPN•HClin solution containing 20 mg/ml pectin (Slendid 100). MannitolBuprenorphine concentration pH detected* Batch No. (mg/ml) (actual)(mg/ml) 036 0 3 (3.2) 13.7 060 12.5 3 (3.1) 13 061 25 3 (3.1) 12.3 06237.5 3 (3.0) 12.4 063 50 3 (3.2) 13.9 037 0 4 (3.9) 16.4 065 12.5 4(4.0) 16.4 066 25 4 (4.0) 15.8 067 37.5 4 (4.0) 15.7 068 50 4 (4.0) 15.5038 0 5 (4.9) 4.4 070 12.5 5 (5.1) 4.9 071 25 5 (5.2) 3.9 072 37.5 5(5.1) 4.6 073 50 5 (5.2) 4.3 039 0 6 (5.9) 1.8 075 12.5 6 (5.9) 2.0 07625 6 (5.6) 1.9 077 37.5 6 (5.6) 2.4 078 50 6 (5.3) 1.8 *Expressed asbuprenorphine free baseNegative Control Experiment: Effect of Mixing HM (High Methoxy) Pectin(20 mg/ml Genu (Trade Mark) Pectin [Citrus] Type USP-H) Solution withCalcium

The pectins suitable for retaining drugs at mucosal surfaces have a lowdegree of esterification (also called “low methoxy” or “LM” pectins)and, in aqueous solution, will gel in the presence of ions found inmucosal fluid, especially divalent ions, in particular calcium. As anegative control, a solution of “high methoxy” pectin was prepared andmixed with a solution containing calcium ions.

1. Methods

Buprenorphine hydrochloride (107.5 mg), anhydrous dextrose (1.25 g) andpectin (Genu pectin [citrus] type USP-H; CP Kelco, Lille Skenved,Denmark) (500 mg) were stirred in 18-20 ml water in a 25 ml volumetricflask overnight or until a solution formed. The mixture was then made upto 25 ml with water to give a solution containing 4 mg/ml buprenorphine,20 mg/ml pectin and 50 mg/ml dextrose and the pH and osmolality weredetermined. A 20 ml aliquot of the formulation was mixed (undercontrolled conditions) with 5 ml of a standard calcium chloride solution(9.44 mg/ml CaCl₂.2H₂O) before standing for 1 hour at room temperature.The structure, uniformity and clarity of the product were thenevaluated.

2. Results

The solution had a pH of 3.3 and an osmolality of 0.35 osmol/kg. Anopaque, pale yellow solution was formed when the solution was mixed with9.44 mg/ml CaCl₂.2H₂0. The solution did not gel even when left for 1hour at room temperature.

Example 8 Clinical Study

Unit doses of the intranasal buprenorphine formulations of Examples 1, 3and (Formulations A to C) and one intravenous commercial buprenorphineformulation (Temgesic-trade mark; Formulation D) were administered tohealthy human volunteers. The unit doses administered to the volunteerswere as follows:

-   -   800 μg buprenorphine hydrochloride, calculated as buprenorphine,        of Formulations A, B or C administered intranasally; and    -   a single slow intravenous injection of 400 μg buprenorphine        hydrochloride, calculated as buprenorphine, of Formulation D.

The dosing was performed on twelve healthy volunteers using arandomised, complete crossover design. Each dose was separated by, atleast, seven days. The volunteers were required to fast overnight priorto dosing. Subjects were admitted to a clinic the evening before eachdose of administration and remained in the clinic until blood samplecollection for each study day. Blood samples were collected at regularintervals up to 24 hours after each dose administration. The volunteerswere discharged from the clinic after completion of all 24 hour studyprocedures. There was a wash out period of, at least seven days, betweeneach dose.

The pharmacokinetics of each dosage regimen were evaluated. The resultsare shown in FIGS. 1 to 3. All three intranasal solutions showed similarpharmacokinetic profiles. The C_(ther) was reached within 5 to 10minutes for each formulation and the C_(max) was reached in 20 minutesor less. The data indicated that the initial plasma peak was blunted forthe intranasal formulations compared to intravenous administration. Thatappeared most pronounced for Formulation A. All three intranasalsolutions gave high bioavailability (Table 11)

TABLE 11 Comparison of key pharmacokinetic parameters derived from theclinical study data on intranasal buprenorphine with published data onthe sublingual tablet and with a dextrose formulation of buprenorphine.Clinical study data (prior art) (prior art) Intranasal Buprenorphinesublingual intranasal 0.8 mg 0.8 mg Buprenorphine Buprenorphine PK 0.8mg Chitosan/ Chitosan/ 0.4 mg 0.5 mg 0.3 mg dextrose Parameter PectinHPMC Poloxamer tablet tablet solution C_(max) (ng/ml) 3.7 4.4 3.8 0.51.04 1.8 T_(max) (min) 20 18 20 210 192 31 Bioavailability 80% 81% 72%56% 48%

A pharmacokinetic profile was computed for a 400 μg intranasal dose ofFormulation A, calculated as buprenorphine, from the data for the 800 μgdose of Formulation A. This profile is shown in FIG. 4. FIG. 4 alsoshows the pharmacokinetic profile for the 400 μg dose of Formulation Athat was administered intravenously.

1.-12. (canceled)
 13. A pharmaceutical composition suitable for use asan analgesic which comprises an analgesic and a delivery agent whereby,on introduction into the nasal cavity of a patient to be treated, theanalgesic is delivered to the bloodstream to produce within 30 minutes atherapeutic plasma concentration C_(ther) of 0.2 ng/ml or greater whichis maintained for a duration T_(maint) of at least 2 hours. 14.-15.(canceled)
 16. An aqueous solution suitable for intranasaladministration, which comprises: (a) from 0.1 to 10 mg/ml ofbuprenorphine or a physiologically acceptable salt or ester thereof, (b)from 0.1 to 20 mg/ml of a chitosan, and (c) from 0.1 to 15 mg/ml ofhydroxypropylmethylcellulose; which solution has a pH of from 3 to 4.8.17. A solution according to claim 16, wherein thehydroxypropylmethylcellulose has an apparent viscosity of from 3000 to6000 cps and is present in an amount of from 0.1 to 15 mg/ml.
 18. Asolution according to claim 17, wherein the hydroxypropylmethylcelluloseis present in an amount of from 0.5 to 10 mg/ml.
 19. An aqueous solutionsuitable for intranasal administration, which comprises: (a) from 0.1 to10 mg/ml of buprenorphine or a physiologically acceptable salt or esterthereof, (b) from 0.1 to 20 mg/ml of a chitosan, and (c) from 50 to 200mg/ml of a polyoxyethylene-polyoxypropylene copolymer of the generalformula HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H wherein a is from 2 to 130and b is from 15 to 67; which solution has a pH of from 3 to 4.8.
 20. Asolution according to claim 19, wherein thepolyoxyethylene-polyoxypropylene copolymer is present in an amount offrom 80 to 120 mg/ml.
 21. A solution according to claim 19, wherein thepolyoxyethylene-polyoxypropyene copolymer has a molecular weight of from7,000 to 10,000.
 22. A solution according to claim 19, wherein thepolyoxyethylene-polyoxypropylene copolymer is one in which a is 80 and bis
 27. 23. A solution according to claim 16, which has an osmolality offrom 0.32 to 0.4 osmol/kg.
 24. A solution according to claim 16, whereinthe buprenorphine or buprenorphine salt or ester is present in an amountof from 0.5 to 8 mg/ml.
 25. A solution according to claim 24, whereinthe buprenorphine or buprenorphine salt or ester is present in an amountof from 1 to 6 mg/ml calculated as buprenorphine.
 26. A solutionaccording to claim 16, which comprises buprenorphine hydrochloride. 27.A solution according to claim 16, wherein the chitosan is present in anamount of from 2 to 10 mg/ml.
 28. A solution according to claim 16,wherein the chitosan is a physiologically acceptable salt of adeacetylated chitin
 29. A solution according to claim 28, wherein thesalt is chitosan glutamate.
 30. A solution according to claim 16,wherein the pH is from 3.2 to 3.8.
 31. A solution according to claim 16,wherein the pH has been adjusted by means of hydrochloric acid.
 32. Asolution according to claim 16, which comprises a preservative.
 33. Asolution according to claim 32, wherein the preservative is benzalkoniumchloride.
 34. A solution according to claim 16, which contains dextroseas a tonicity adjustment agent. 35.-37. (canceled)
 38. An aqueoussolution suitable for intranasal administration, which comprises from0.1 to 10 mg/ml of buprenorphine or a physiologically acceptable salt orester thereof and from 5 to 40 mg/ml of a pectin having a degree ofesterification of less than 50%; which solution has a pH of from 3 to4.2, is substantially free from divalent metal ions and gels on thenasal mucosa.
 39. A solution according to claim 38, wherein thebuprenorphine or buprenorphine salt or ester is present in an amount offrom 0.5 to 8 mg/ml.
 40. A solution according to claim 39, wherein thebuprenorphine or buprenorphine salt or ester is present in an amount offrom 1 to 6 mg/ml calculated as buprenorphine.
 41. A solution accordingto claim 38, which comprises buprenorphine hydrochloride.
 42. A solutionaccording to any claim 38, wherein the pectin is present in an amount offrom 10 to 30 mg/ml.
 43. A solution according to claim 38, wherein thepectin has a degree of esterification of from 10 to 35%.
 44. A solutionaccording to claim 38, wherein the pH is from 3.2 to 3.8.
 45. A solutionaccording to claim 38, wherein the pH has been adjusted by means ofhydrochloric acid.
 46. A solution according to claim 38, which comprisesa preservative.
 47. A solution according to claim 46, which comprisesphenylethyl alcohol and propyl hydroxybenzoate as preservatives.
 48. Asolution according to claim 38, which has an osmolality of from 0.25 to0.4 osmol/kg.
 49. A solution according to claim 38, which containsdextrose as a tonicity adjustment agent.
 50. An aqueous solutionsuitable for intranasal administration, which has a pH of from 3.5 to4.0, which is substantially free from divalent metal ions and whichcomprises: (a) from 1 to 6 mg/ml of buprenorphine or a physiologicallyacceptable salt or ester thereof, calculated as buprenorphine, (b) from10 to 40 mg/ml of a pectin which has a degree of esterification from 10to 35%, and (c) dextrose as a tonicity adjustment agent. 51.-52.(canceled)
 53. A nasal delivery device loaded with a solution as claimedin claim
 16. 54. A device according to claim 53, which is a spraydevice. 55.-56. (canceled)
 57. A method of inducing analgesia in apatient in need thereof, which method comprises administeringintranasally to said patient a pharmaceutical composition, whichcomprises an opioid analgesic and a delivery agent in the form of anaqueous solution; whereby, on introduction of said composition into thenasal cavity of the patient to be treated, the analgesic is delivered tothe bloodstream to produce within 30 minutes a therapeutic plasmaconcentration C_(ther) of 0.2 ng/ml or greater which is maintained for aduration T_(maint) of at least 2 hours, and wherein the delivery agentis from 5 to 40 mg/ml, based on the composition, of a pectin having adegree of esterification of less than 50% provided that the compositionis substantially free of divalent metal ions.
 58. A method according toclaim 57, wherein on introduction of the composition into the nasalcavity of the patient to be treated, the analgesic is delivered to thebloodstream to produce within 2 to 15 minutes a therapeutic plasmaconcentration C_(ther) of 0.4 ng/ml or more which is maintained for aduration T_(maint) of 2 to 4 hours.
 59. A method according to claim 57,wherein the pectin has a degree of esterification of from 10 to 35%. 60.A method according to claim 57, wherein C_(ther) is from 0.4 to 100ng/ml and is produced within 1 to 15 minutes.
 61. A method according toclaim 57, wherein C_(max) is reached 10 to 30 minutes after introductionof said composition into the nasal cavity of the patient to be treated.62. A method according to claim 57, wherein the composition is deliveredusing a nasal delivery device.
 63. A method according to claim 62,wherein on introduction of the composition into the nasal cavity of apatient to be treated, the analgesic is delivered to the bloodstream toproduce within 2 to 15 minutes a therapeutic plasma concentrationC_(ther) of 0.4 ng/ml or more which is maintained for a durationT_(maint) of 2 to 4 hours.
 64. A method according to claim 57, whereinthe opioid analgesic is fentanyl.